NOX2 decoy peptides disrupt trauma-mediated neutrophil immunosuppression and protect against lethal peritonitis

Abstract

Trauma and sepsis are frequent causes of immunosuppression and risk of secondary bacterial infections and mortality among critically ill patients. Reduced activity of neutrophil NADPH oxidase 2 (NOX2) and impaired bacterial killing are among the major indices of immunosuppression. We hypothesize that NOX2-decoy peptides disrupt the inhibition of neutrophil NOX2 by plasma of patients with severe trauma and immunosuppression, thereby preserving the neutrophil respiratory burst that is a central antimicrobial mechanism. We demonstrate that plasma from trauma/hemorrhage (T/H) patients, but not healthy donors (HD), significantly reduced the activity of neutrophil NOX2 and impaired bacterial killing. The inhibitory action of plasma was associated with an increase in bacterial infections among trauma survivors. High Mobility Group Box 1 (HMGB1) is a mediator of lethality in trauma and sepsis and our mechanistic studies revealed that disulfide and oxidized forms of HMGB1 bind to the gp91 phox subunit of NOX2, and thus decrease the neutrophil respiratory burst and bacterial killing. NOX2 decoy Anti-Immunosuppression (Ai) Peptides 1 and 3 effectively disrupted the immunosuppressive action of T/H plasma. HMGB1 selectively binds to Ai-Peptide 3, supporting the possibility for direct interaction between HMGB1 and the third external loop of gp91 phox . In vivo , Ai-Peptides improved survival of mice subjected to lethal peritonitis. Taken together, plasma-dependent inhibition of neutrophil NOX2 appeared to be a suitable indicator of immunosuppression in patients with severe trauma. Given that gp91 phox decoys protected the neutrophil respiratory burst, selected Ai-Peptides have therapeutic potential to reduce bacterial infections and end-organ injury associated with sepsis/trauma-induced immunosuppression.

Machine learning-based identification of CYBB and FCAR as potential neutrophil extracellular trap-related treatment targets in sepsis

“…Husain et al. ( 36 ) found that inhibiting CYBB could not only reduce neutrophil immunosuppression in critically ill patients with sepsis, but also reduce sepsis bacterial infection and organ damage, similar to the findings of our study. Inhibition of CYBB can also inhibit microglial activation and improve cognitive impairment after sepsis ( 37 ), as well as promoting sepsis myocardial injury through the ERK1/2-TNFα pathway ( 38 ).…”

“…Further, we used bioinformatics analysis to predict that elevated CYBB will lead to increased mPTP, thereby increasing NETs. Husain et al (36) found that inhibiting CYBB could not only reduce neutrophil immunosuppression in critically ill patients with sepsis, but also reduce sepsis bacterial…”

AMPK activates Parkin independent autophagy and improves post sepsis immune defense against secondary bacterial lung infections

“…Male C57BL/6 mice and C57BL/6 Park2 −/− mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Mice were given food and water ad libitum and kept on a 12-h light–dark cycle 26 , 27 . Mice 10 to 12 weeks of age were used for primary neutrophils and macrophages as well as to conduct experiments with metformin and sepsis-induced immunosuppression/secondary bacterial lung infections.…”

Bioenergetic maladaptation and release of HMGB1 in calcineurin inhibitor-mediated nephrotoxicity

“…[50][51][52][53] Indeed, our results suggest that HMGB1 is released in parallel to mitochondrial ROS formation. Recent studies indicate that oxidation of HMGB1 contributed to HMGB1 translocation and extracellular flux, 54 although we did not test HMGB1 posttranslational modifications. These finding support a possibility that CNIinduced mitochondrial ROS can promote HMGB1 oxidation and AJT release.…”